| Targeted PPAR{gamma} deficiency in alveolar macrophages disrupts surfactant catabolism. | |
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MedLine Citation:
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PMID: 20064973 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Surfactant accumulates in alveolar macrophages of granulocyte-macrophage colony-stimulating factor (GM-CSF) knockout (KO) mice and pulmonary alveolar proteinosis (PAP) patients with a functional loss of GM-CSF resulting from neutralizing anti-GM-CSF antibody. Alveolar macrophages from PAP patients and GM-CSF KO mice are de-ficient in peroxisome proliferator-activated receptor-gamma (PPARgamma) and ATP-binding cassette (ABC) lipid transporter ABCG1. Previous studies have demonstrated that GM-CSF induces PPARgamma. We therefore hypothesized that PPARgamma promotes surfactant catabolism through regulation of ABCG1. To address this hypothesis, macrophage-specific PPARgamma (MacPPARgamma) knockout mice were utilized. MacPPARgamma KO mice develop foamy, lipid-engorged Oil Red O positive alveolar macrophages. Lipid analyses revealed significant increases in the cholesterol and phospholipid contents of MacPPARgamma KO alveolar macrophages and extracellular bronchoalveolar lavage (BAL)-derived fluids. MacPPARgamma KO alveolar macrophages showed decreased expression of ABCG1 and a deficiency in ABCG1-mediated cholesterol efflux to HDL. Lipid metabolism may also be regulated by liver X receptor (LXR)-ABCA1 pathways. Interestingly, ABCA1 and LXRbeta expression were elevated, indicating that this pathway is not sufficient to prevent surfactant accumulation in alveolar macrophages. These results suggest that PPARgamma mediates a critical role in surfactant homeostasis through the regulation of ABCG1. |
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Authors:
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Anna D Baker; Anagha Malur; Barbara P Barna; Shobha Ghosh; Mani S Kavuru; Achut G Malur; Mary Jane Thomassen |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2010-01-11 |
Journal Detail:
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Title: Journal of lipid research Volume: 51 ISSN: 0022-2275 ISO Abbreviation: J. Lipid Res. Publication Date: 2010 Jun |
Date Detail:
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Created Date: 2010-05-12 Completed Date: 2010-08-17 Revised Date: 2011-07-28 |
Medline Journal Info:
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Nlm Unique ID: 0376606 Medline TA: J Lipid Res Country: United States |
Other Details:
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Languages: eng Pagination: 1325-31 Citation Subset: IM |
Affiliation:
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Department of Internal Medicine, East Carolina University, Greenville, NC, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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ATP-Binding Cassette Transporters
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metabolism Animals Cholesterol / metabolism Gene Knockout Techniques Lipoproteins / metabolism Lipoproteins, HDL / metabolism Lung / metabolism Macrophages, Alveolar / metabolism* Mice Organ Specificity Orphan Nuclear Receptors / metabolism PPAR gamma / deficiency*, genetics* Surface-Active Agents / metabolism* |
| Chemical | |
Reg. No./Substance:
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0/ABCG1 protein, mouse; 0/ATP-Binding Cassette Transporters; 0/Lipoproteins; 0/Lipoproteins, HDL; 0/Orphan Nuclear Receptors; 0/PPAR gamma; 0/Surface-Active Agents; 0/liver X receptor; 57-88-5/Cholesterol |
| Comments/Corrections | |
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